Abstract

Insulin resistance (IR) seems to play a major role both in the evolution towards diabetes, and in affecting myocardial performance and endothelial function. Has been showed
metformin (MET) therapy exert positive effect improving glucidic tolerance and preventing the evolution toward diabetes; nevertheless, it is known that MET may reduce maxVO2 consumption in an healthy population. Recently has been shown that adding metformin to exercise training did
not improve insulin sensitivity, and it may have blunted the full effects of exercise training. The aim of this study was to determine the effect of combining exercise training with metformin on cardiometabolic performance in individuals with IR, compared with either treatment alone.
Methods: out of population of 102 patients, 25 IR consecutive patients (9 females and 16 males; mean age 46±11 years) (HOMA=5±3.5) were enrolled to perform a cardiopulmonary exercise test and peripheral arterial tonometry, to measure the endothelial flow reserve (EFR), at baseline and after metformin. Insulin resistance was computed (HOMA-IR) before and after 12 weeks of each
intervention. The other IR patients were randomly assigned to metformin (M) (n=17), metformin with exercise training (ME) (n=11), and exercise training alone (E) (n =12 ). CPET (cardiopulmonary exercise test) and SF-36 to evaluate Health-Related Quallity of Life was performed at basal and after 12-weeks of treatment. Results: Mean value of VO2 peak at enrollment was reduced in comparison with the theoretic values of an healthy population (61,66 % ± 13).
Inter-test comparison performed at baseline and after 3 months of metformin revealed a slight reduction in BMI (29±5 vs 30±5, p<0.05), a significant increase in EFR (2.13±0.29 vs 1.93±0.44, p<0.05), and a significant reduction in VO2 (1.48±0.37 l/min vs 1.60±0.44 l/min, p=0.03). Nevertheless, the decline in peak VO2 was not displayed by the entire patient sample: 11 subjects
(group A) featured an increase in peak VO2, whilst 9 (group B) presented a decrease. A significant difference in HOMA index was detected between these 2 groups, with higher values in group A (7.8±3.5) than group B (3.3±0.7; p<0.001).
BMI was significantly reduced only in ME (31,5±4 vs 29,55±3,98; p<0,05) and M (29,75 ± 4,77 vs 28,4 ± 4,59; p<0,05) groups. CPET showed a significant increase of peakVO2 in E and ME whereas M showed no improvement of peak VO2 (∆ VO2 E +0,35 ± 0,46, p<0,05; ∆ VO2 ME +0,23 ± 0,31,
p<0,05; ∆ VO2 M -0,09 ± 0,13, p= < 0,05; M vs E p<0,01; M vs ME p<0,01; ME vs E p = ns). ME group showed a significant increase of Work compared respectively with M and E group (∆Work E +8,00 ± 16,42; ∆Work ME +23,00 ± 22,21; ∆Work M -2,92 ± 17,14; M vs E p=ns; M vs ME p<0,05, E
vs ME p=ns). SF-36 highlighted a significant increase in general Quallity of Life index in ME and E groups without differences between the two groups. Conclusions: Our study confirms that IR favors an impairment of cardiometabolic performance. The data obtained show that in IR patients metformin reduces average oxygen consumption to a
modest but significant extent. Indeed, it is of particular interest to observe how this effect was not manifested by all subjects, being present only in patients featuring a lower degree of IR, while patients with higher IR cardiopulmonary performance was significantly improved.
The negative effects showed by metformin therapy may be counterbalanced with the association of exercise training. Exercise training alone produced similar effects to the association of exercise training and Metformin in terms of cardiopulmonary performance and quality of life. The
additional benefits of improving effort tolerance and improving Health-Related Quallity of Life, contribute to identify the supervised training as a reliable and effective component in the management of IR population.
Therefore our conclusions are that the best treatment in IR patients is exercise training. More extensive studies are needed to show the real benefits of Metformin and exercise training association.

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